Wood Michael R, Noetzel Meredith J, Tarr James C, Rodriguez Alice L, Lamsal Atin, Chang Sichen, Foster Jarrett J, Smith Emery, Chase Peter, Hodder Peter S, Engers Darren W, Niswender Colleen M, Brandon Nicholas J, Wood Michael W, Duggan Mark E, Conn P Jeffrey, Bridges Thomas M, Lindsley Craig W
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2016 Sep 1;26(17):4282-6. doi: 10.1016/j.bmcl.2016.07.042. Epub 2016 Jul 21.
This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.
本信函描述了基于非烯醇化酮核心的一系列新型M4型正变构调节剂（PAMs）的化学优化过程，该系列化合物是从分子文库药物化学中心（MLPCN）功能性高通量筛选中鉴定出来的。高通量筛选得到的活性化合物具有高效、高选择性且能够穿透血脑屏障；然而，该化合物在体外和体内均被快速清除。构效关系（SAR）研究提供了一系列类似物，这些类似物保留了M4型PAM的活性和中枢神经系统暴露量；然而，清除率仍然很高。代谢物鉴定研究表明，该系列化合物会快速且几乎定量地还原代谢为相应的仲醇代谢物，而该代谢物不具有M4型PAM活性。
